Role Of Asymmetric Dimethylarginine Research Articles

Association between protein arginine N-methyltransferase 1 polymorphism and overt diabetic nephropathy: Role of asymmetric dimethylarginine in vascular tone

Backgroundω-NG,NG-asymmetric dimethylarginine (ADMA) regulates vascular tone and may participate in the pathogenesis of diabetic nephropathy (DN). ObjectiveTo investigate whether single-nucleotide polymorphisms (SNPs) around the protein arginine N-methyltransferase 1 gene (PRMT1) influence ADMA dynamics and DN incidence and severity. MethodsThis study utilized a hospital-based database containing 310 Japanese patients with type 2 diabetes mellitus (T2DM). The association of PRMT1-related tagged SNPs with DN stage distribution was examined using a dominant model of minor alleles. PRMT1 mRNA, serum ADMA, reactive hyperemia-peripheral arterial tonometry index (RHI), and brachial-ankle pulse wave velocity (baPWV) were compared between the genotype-based subgroups of causal SNP, and correlations between these variables were evaluated. ResultsThe composition of DN stages significantly differed between the GG and GA + AA subgroups of rs892151 (p = 0.026). In a propensity-matching cohort of rs892151, the GA + AA subgroup had an increased incidence of overt DN (odds ratio 2.92, 95 % confidence interval 1.12–7.62, p = 0.028), along with higher PRMT1 mRNA, serum ADMA levels, and baPWV than the GG subgroup (p < 0.001, p = 0.023 and 0.047, respectively). There were correlations between PRMT1 mRNA and serum ADMA levels, between serum ADMA levels and RHI, and between baPWV and urinary albumin excretion (r = 0.335, p < 0.001, r = -0.221, p = 0.029, and r = 0.254, p = 0.004, respectively). ConclusionsT2DM patients carrying the PRMT1-related variant rs892151 were susceptible to overt DN. ADMA-mediated endothelial dysfunction and arterial stiffness may be involved in the variant-related pathogenesis of overt DN.

LncRNA DANCR deficiency promotes high glucose-induced endothelial to mesenchymal transition in cardiac microvascular cells via the FoxO1/DDAH1/ADMA signaling pathway

Cardiac fibrosis is the main pathological basis of diabetic cardiomyopathy (DCM), and endothelial-to-meschenymal transition (EndMT) is a key driver to cardiac fibrosis and plays an important role in the pathogenesis of DCM. Asymmetric dimethylarginine (ADMA), a crucial pathologic factor in diabetes mellitus, is involved in organ fibrosis. This study aims to evaluate underlying mechanisms of ADMA in DCM especially for EndMT under diabetic conditions. A diabetic rat model was induced by streptozotocin (STZ) injection, and human cardiac microvascular endothelial cells (HCMECs) were stimulated with high glucose to induce EndMT. Subsequently, the role of ADMA in EndMT was detected either by exogenous ADMA or by over-expressing dimethylarginine dimethylaminohydrolase 1 (DDAH1, degradation enzyme for ADMA) before high glucose stimulation. Furthermore, the relationships among forkhead box protein O1 (FoxO1), DDAH1 and ADMA were evaluated by FoxO1 over-expression or FoxO1 siRNA. Finally, we examined the roles of LncRNA DANCR in FoxO1/DDAH1/ADMA pathway and EndMT of HCMECs. Here, we found that EndMT in HCMECs was induced by high glucose, as evidenced by down-regulated expression of CD31 and up-regulated expression of FSP-1 and collagen Ⅰ. Importantly, ADMA induced EndMT in HCMECs, and over-expressing DDAH1 protected from developing EndMT by high glucose. Furthermore, we demonstrated that over-expression of FoxO1-ADA with mutant phosphorylation sites of T24A, S256D, and S316A induced EndMT of HCMECs by down-regulating of DDAH1 and elevating ADMA, and that EndMT of HCMECs induced by high glucose was reversed by FoxO1 siRNA. We also found that LncRNA DANCR siRNA induced EndMT of HCMECs, activated FoxO1, and inhibited DDAH1 expression. Moreover, over-expression of LncRNA DANCR could markedly attenuated high glucose-mediated EndMT of HCMECs by inhibiting the activation of FoxO1 and increasing the expression of DDAH1. Collectively, our results indicate that LncRNA DANCR deficiency promotes high glucose-induced EndMT in HCMECs by regulating FoxO1/DDAH1/ADMA pathway.

Role of ADMA in the pathogenesis of microvascular complications in type 2 diabetes mellitus.

Diabetic microangiopathy is a typical and severe problem in diabetics, including diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, and diabetic cardiomyopathy. Patients with type 2 diabetes and diabetic microvascular complications have significantly elevated levels of Asymmetric dimethylarginine (ADMA), which is an endogenous inhibitor of nitric oxide synthase (NOS). ADMA facilitates the occurrence and progression of microvascular complications in type 2 diabetes through its effects on endothelial cell function, oxidative stress damage, inflammation, and fibrosis. This paper reviews the association between ADMA and microvascular complications of diabetes and elucidates the underlying mechanisms by which ADMA contributes to these complications. It provides a new idea and method for the prevention and treatment of microvascular complications in type 2 diabetes.

The role of asymmetric dimethylarginine in endothelial dysfunction and abnormal nitric oxide metabolism in systemic sclerosis: results from a pilot study.

Systemic sclerosis (SSc) is characterized by generalized vasculopathy affecting mainly small vessels while macrovascular involvement is less investigated. The aim of this study was to examine associations between asymmetric dimethylarginine (ADMA) - a biomarker of atherosclerosis - and assessments of macrovascular endothelial function in patients with SSc. This was a cross-sectional study including consecutive SSc patients attending the Scleroderma Outpatient Clinic. ADMA measurement in serum samples was based on an enzyme immunoassay technique. Participants underwent blood pressure measurement according to 2018 ESC/ESH Guidelines, applanation tonometry for the evaluation of arterial stiffness, and carotid ultrasound for the measurement of the intima-media thickness (cIMT). Eighty-one Caucasians (82.3% female) SSc individuals with mean age 55.44 ± 13.4years were included in this analysis. The correlation analysis of ADMA levels (unadjusted and adjusted values) with functional and morphological parameters of atherosclerosis revealed no statistically significant associations. Subgroup analysis based on disease duration (≤ 4years), immunologic profile (SCL-70 and ACA antibodies), disease type (limited, diffuse), and inflammatory status (erythrocyte sedimentation rate [ESR] > 25mm/h and C-reactive protein [CRP] > 5mg/L) showed no associations, except from a significant positive correlation between ADMA levels and cΙΜΤmean (r = 0.370, p = 0.044) in individuals with early SSc. The results of the study suggest that ADMA may be related with accelerated atherosclerosis in early stages of the disease. However, the lack of association between other morphological and functional parameters of endothelial dysfunction may suggest that other regulators of nitric oxide metabolism may contribute to macrovascular injury in SSc in various phases of the disease. Key Points • ADMA is a biomarker of atherosclerosis and has been linked with microvascular complications of SSc. •ADMA was not correlated with morphological and functional parameters of atherosclerosis in the population of the study. •The demonstrated association between ADMA and cIMT in patients with early SSc may suggest a role of NO/ADMA pathway in the initiation of macrovascular injury in SSc.

A Recombinant Dimethylarginine Dimethylaminohydrolase-1-Based Biotherapeutics to Pharmacologically Lower Asymmetric Dimethyl Arginine, thus Improving Postischemic Cardiac Function and Cardiomyocyte Mitochondrial Activity.

High serum levels of asymmetric dimethyl arginine (ADMA) are associated with cardiovascular disease and mortality. Pharmacological agents to specifically lower ADMA and their potential impact on cardiovascular complications are not known. In this study, we aimed to investigate the effect of specific lowering of ADMA on myocardial response to ischemia-reperfusion injury (I/R) and direct effects on cardiomyocyte function. Effects of recombinant dimethylarginine dimethylaminohydrolase (rDDAH)-1 on I/R injury were determined using isolated mouse heart preparation. Respiration capacity and mitochondrial reactive oxygen species (ROS) generation were determined on mouse cardiomyocytes. Our results show that lowering ADMA by rDDAH-1 treatment resulted in improved recovery of cardiac function and reduction in myocardial infarct size in mouse heart response to I/R injury (control 22.24 ±4.60% versus rDDAH-1 15.90 ±4.23%, P < 0.01). In mouse cardiomyocytes, rDDAH-1 treatment improved ADMA-induced dysregulation of respiration capacity and decreased mitochondrial ROS. Furthermore, in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes with impaired contractility under hypoxia and high ADMA, rDDAH-1 treatment improved recovery and beating frequency (P < 0.05). rDDAH-1 treatment selectively modified I/R-induced myocardial cytokine expression, resulting in reduction in proinflammatory cytokine IL-17A (P < 0.001) and increased expression of anti-inflammatory cytokines IL-10 and IL-13 (P < 0.01). Further in vitro studies showed that IL-17A was the predominant and common cytokine modulated by ADMA-DDAH pathway in heart, cardiomyocytes, and endothelial cells. These studies show that lowering ADMA by pharmacological treatment with rDDAH-1 reduced I/R injury, improved cardiac function, and ameliorated cardiomyocyte bioenergetics and beating activity. These effects may be attributable to ADMA lowering in cardiomyocytes and preservation of cardiomyocyte mitochondrial function. SIGNIFICANCE STATEMENT: The pathological role of asymmetric dimethyl arginine (ADMA) has been demonstrated by its association with cardiovascular disease and mortality. Currently, pharmacological drugs to specifically lower ADMA are not available. The present study provides the first evidence that lowering of ADMA by recombinant recombinant dimethylarginine dimethylaminohydrolase (rDDAH)-1 improved postischemic cardiac function and cardiomyocyte bioenergetics and beating activity. Our studies suggest that lowering of ADMA by pharmacologic treatment offers opportunity to develop new therapies for the treatment of cardiovascular and renal disease.

Endothelial dysfunction biomarkers in sickle cell disease: is there a role for ADMA and PAI-1?

Within the spectrum of sickle cell disease (SCD) are sickle cell anemia (SCA), presence of hemoglobin SS (HbSS), hemoglobin SC disease (HbSC), and sickle cell β-thalassemia (Sβ-thal). Asymmetric dimethylarginine (ADMA) competitively inhibits the binding of arginine to NOS, reducing NO production. In patients with HbSS, increased levels of ADMA have been reported, as well as changes in many hemostatic biomarkers, including the plasminogen activator inhibitor type 1 (PAI-1). We hypothesized that high levels of ADMA and PAI-1 may be associated with more severe SCD. Thus, ADMA and PAI-1 levels were determined in 78 individuals including 38 adult patients with SCD and 40 control subjects. Higher levels of ADMA were shown in HbSS and Sβ-thal patients compared to controls. Concerning PAI-1, all patients showed high levels of PAI-1 compared to controls. As a role of NO in the pathogenesis of SCD has already been established, we concluded that high levels of ADMA should compromise, at least in part, NO synthesis, resulting in endothelial dysfunction. Elevated plasma levels of PAI-1 in all patients may indicate not only endothelial dysfunction but also a hypofibrinolytic state favoring thrombotic complications. Finally, high levels of ADMA and PAI-1 may be associated with more severe SCD.

The Role of Oxidative Stress Markers in Predicting Acute Thrombotic Occlusion of Haemodialysis Vascular Access and Progressive Stenotic Dysfunction Demanding Angioplasty.

Haemodialysis vascular access (VA) dysfunction is a major cause of morbidity in haemodialysis (HD) patients. Primary venous outflow occlusion and restenosis after percutaneous transluminal angioplasty (PTA) are two major obstacles for the long-term use of dialysis VA. It remains unclear whether oxidative stress markers can be used as predictors for thrombotic occlusion of VA and progressive stenosis dysfunction demanding PTA. All routine HD patients at one teaching hospital participated in this study including ankle-brachial index (ABI) examinations and serum oxidative stress markers. The serum oxidative stress markers (high-sensitivity C-reactive protein (hs-CRP), matrix metalloproteinase-2 (MMP-2), MMP-9, homocysteine, asymmetrical dimethylarginine (ADMA), nitrate oxidase (NO), tumour necrosis factor-α (TNF-α), monocyte chemotactic protein 1 (MCP-1), interleukin-1β (IL-1β), and transforming growth factor-β (TGF-β)) were measured using immunosorbent assays in 159 HD patients (83 men and 76 women; mean age: 65 ± 12 years). The participants met the following criteria: (1) received regular HD treatment for at least 6 months, without clinical evidence of acute or chronic inflammation, recent myocardial infarction, unstable angina or circulatory congestion; and (2) received an arteriovenous fistula (AVF)/arteriovenous graft (AVG: polytetrafluoroethylene, PTFE) as the current VA for more than 6 months, without interventions within the last 6 months. All the participants were followed up clinically for up to 12 months to estimate the amount of primary thrombotic occlusion and VA dysfunction demanding PTA. During the 12-month observation, 24 patients (15.1%) had primary thrombotic occlusion of VAs. Another 24 patients (15.1%) required PTA because of clinical dysfunction of access. Additionally, during the follow-up period, restenosis occurred in 12 patients (50% of 24 patients). The access types of arteriovenous grafts (AVGs) and a diagnosis of peripheral arterial occlusive disease (PAOD) were two strong predictors for acute thrombotic events of VA (hazard ratio (HR): 16.93 vs. 2.35; p < 0.001 vs. 0.047). Comparing dysfunctional with non-dysfunctional VAs, up to 27.7% of patients with high levels of ADMA (>0.6207 μM, N = 65) received required PTA compared with 4.4% of those with low levels (≤0.6207 μM; N = 90; p < 0.001). In multivariate analysis, the plasma baseline levels of ADMA independently conferred nearly 4.55 times the risk of primary stenotic dysfunction of HD VA (HR: 4.55; 95% confidence interval: 1.20 to 17.26; p = 0.026). In conclusion, our findings suggest the role of ADMA in the development of symptomatic VA dysfunction. Additionally, PAOD severity can be used in clinical practice to predict whether acute thrombotic occlusion of VA will easily occur in HD patients.

The role of asymmetric dimethylarginine (ADMA) in the follow-up of patients with precapillary pulmonary hypertension (PH)

Abstract Introduction Asymmetric dimethylarginine (ADMA) interferes with L-arginine in the production of nitric oxide, a key mediator of endothelial cell function. ADMA is elevated in pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) and is associated with unfavorable outcomes. Aim To assess the role of ADMA to monitor disease progression of PH patients treated with PAH-specific therapy. Methods ADMA was measured by competitive ELISA at baseline (BL) and follow-up (FU). Risk assessment including a clinical assessment, echocardiography, 6-minute walking test, NT-pro-BNP and hemodynamic assessment by right heart catheterization was performed accordingly. Risk was calculated according to the ESC/ERS 2015 guidelines by the SPHAR method. Results ADMA samples were collected from 113 patients treated at our institution between 2012 and 2019. 89 (79%) patients had PAH, 15 (13%) were diagnosed with CTEPH and 9 (8%) with group 3 – PH associated with lung disease. 69% were females. 15 (13.3%) patients had a low risk at baseline, 96 (85%) intermediate risk and 2 (1.8%) were high risk patients. 75% received oral medications, 31% received subcutaneous treprostinil. Median baseline ADMA was 0.738umol/l. At BL no significant difference of ADMA plasma levels was found among the different PH types (p=0.063), or between different risk categories (p=0.531). Change in ADMA plasma levels correlated with change in risk (p=0.002, rs 0.291) and with change in mixed venous saturation (p=0.034, rs −0.205). Change in ADMA plasma levels also correlated with risk at FU (p=0.011, rs 0.240). Patients categorized as low risk at FU had a median ADMA plasma level decrease of 22%, compared with −3 to 0% ADMA plasma level change in patients with moderate to high risk at FU (p=0.04). Patients who improved their risk category had a median decrease of ADMA plasma level of 23% vs. 2.3% in patients who did not improve (p=0.011). Decrease of ADMA plasma levels was a weak but significant discriminator for improvement of risk in ROC analysis (p=0.032, AUC 0.374). Conclusion ADMA plasma levels paralleled the hemodynamic and clinical benefit of PAH-specific treatments in patients with precapillary PH. ADMA could be used as a biomarker for monitoring treatment effects in precapillary PH. Funding Acknowledgement Type of funding source: None

Evaluation of the Correlation between Serum Concentrations of Asymmetric Dimethylarginine and Corrected TIMI Frame Count in Patients with Slow Coronary Flow.

Coronary slow flow (CSF) is an important angiographic entity that is characterized by delayed opacification of coronary arteries in the absence of epicardial occlusive disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. Elevated levels of ADMA cause the induction of endothelial dysfunction and thus promote atherosclerosis. This study was aimed at determining the role of ADMA in the development of CSF. One hundred twenty-nine subjects who fulfilled the inclusion criteria were enrolled in this study. According to coronary angiography results, these subjects were divided into five groups. The serum concentration of ADMA was measured in these subjects. In this study, there was no significant correlation between serum concentrations of ADMA and mean corrected TIMI frame count (CTFC) (P > 0.05). However, the ADMA level was significantly correlated with CTFC in the left anterior descending (LAD) coronary artery in patients with CSF (r = −0.381, P = 0.045). Also, plasma ADMA levels were significantly higher in patients with CSF and without CAD compared to patients without CSF and with CAD (50-90%) (P = 0.034). Besides, serum concentrations of ADMA were significantly higher in subjects with BMI < 25 kg/m2 compared with those having BMI > 30 kg/m2 (P = 0.003). It was also shown that the levels of ADMA were significantly higher in subjects with age as a cardiovascular risk factor compared with those without this risk factor (P = 0.024). Further studies with larger population sizes are needed to confirm the present findings on the association between the serum concentrations of ADMA and CSF.

Role of Asymmetric Dimethylarginine and Nitric Oxide in Type 2 Diabetes Mellitus and Its Cardiovascular Complications

AN ENDOGENOUS inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), is elevated in patients with type 2 diabetes mellitus (T2DM) and has been related to atherosclerotic disease. The study aims at investigating the status of ADMA and nitric oxide (NO) and their possible correlation inpatients with T2DM with and without cardiovascular complicationsin comparison to normalcontrols. Forty patients with T2DM and 20 age, sex and body mass index (BMI)‑matched healthy controls were included in the study. The studied individuals were divided into Group1: healthy controls (n= 20), Group 2: T2DM patients without cardiovascular complications (n= 20) and Group 3: T2DM patients with evidence of cardiovascular complications (n= 20). Serum ADMA levels were determined by enzyme linked Immunosorbent Assay (ELISA). Serum nitric oxide was measured as stable end product, nitrite. Insulin was measured by immunoradiometric method. Serum ADMA levels showed a significant elevation while serum NO levels were significantly reducedin diabetic patients groups in comparison to controls. Diabetic patients with vascular complications showed highly significant increase in ADMA levels and pronounced decrease in NO compared to those without complications. In the group of vascular complications, the ADMA level was positively correlated with postprandial serum glucose and HbA1c, but there was a negative correlation between ADMA levels and NO. ADMA and NO may serve as predictors for future cardiovascular events in T2DM patients. Further studies are required to establish the utility of decreasing ADMA levels or increasing NO in the management of T2DM patients.

Reduced asymmetric dimethylarginine accumulation through inhibition of the type I protein arginine methyltransferases promotes renal fibrosis in obstructed kidneys.

The role of asymmetric dimethylarginine (ADMA) in chronic kidney disease (CKD) is unclear. Through inhibition of type I protein arginine methyltransferases (PRMTs), a novel strategy, we aimed to determine the effect of ADMA on renal fibrosis and explore its underlying working mechanisms. After sham or unilateral ureter ligation (UUO) operation, 20-25 g male c57 mice were treated with vehicle or PT1001B, an inhibitor of type I PRMTs, for 13 d. Moreover, human kidney 2 (HK2) and normal rat kidney 49F (NRK-49F) cells were treated with various concentrations of PT1001B or ADMA in the presence of 2.5 ng/ml TGF-β. We found that treatment with PT1001B increased the deposition of extracellular matrix proteins, the expression of α smooth muscle actin, and connective tissue growth factor in UUO-induced fibrotic kidneys, which is correlated with reduced expression of PRMT1, reduced the production of ADMA, and increased expression of uromodulin. In TGF-β-stimulated HK2 and NRK-49F cells, PT1001B dose-dependently inhibited ADMA production, increased NO concentrations, and enhanced the expression of profibrotic proteins. Exogenous addition of ADMA inhibited the expression of profibrotic proteins dose-dependently and attenuated the profibrotic effect of PT1001B. Moreover, ADMA reduced the NO concentration in PT1001B-treated HK2 cells. Finally, we conclude that ADMA has an antifibrotic effect in obstructed kidneys, and future application of type I PRMT inhibitor should be done cautiously for patients with CKD.-Wu, M., Lin, P., Li, L., Chen, D., Yang, X., Xu, L., Zhou, B., Wang, C., Zhang, Y., Luo, C., Ye, C. Reduced asymmetric dimethylarginine accumulation through inhibition of the type I protein arginine methyltransferases promotes renal fibrosis in obstructed kidneys.

Elevated circulating asymmetric dimethylarginine levels in rheumatoid arthritis: a systematic review and meta-analysis.

Rheumatoid arthritis (RA) patients have increased risk of cardiovascular disease (CVD) death. Elevated asymmetric dimethylarginine (ADMA) levels have been reported to be an independent predictor of CVD morbidity and mortality, however, the role of ADMA in RA remains undetermined. To derive a more accurate estimation on circulating ADMA levels in RA patients, a meta-analysis was performed. Embase, PubMed, and The Cochrane Library database (up to October 7 2018) were used to acquire published literatures. Heterogeneity test was performed by the Q statistic and quantified using I2. Publication bias was evaluated using a funnel plot and Egger's linear regression test. A total of 174 articles were identified, 16 studies with 1365 subjects (666 RA patients and 699 healthy individuals) were ultimately included. Plasma/serum ADMA levels appeared to be higher in RA patients than healthy controls (SMD = 0.84, 95% CI 0.32, 1.35). By assessing the BMI, age, disease duration and disease activity as subgroups, BMI ≥ 24 and BMI < 24 groups both showed elevated ADMA levels than controls, disease duration ≥ 8, age < 50 and disease activity ≥ 3.2 and < 5.1 group had a higher ADMA level than control groups. However, disease duration < 8, disease activity ≥ 5.1 and age ≥ 50 groups showed no difference between two groups. Circulating ADMA levels are higher in RA patients compared with healthy controls. In addition, ADMA levels are influenced by age, disease duration and disease activity.

Excessive Ultrafiltration During Hemodialysis Plays a Role in Intradialytic Hypertension Through Decreased Serum Nitric Oxide (NO) Level

Background: Intradialytic hypertension is one of many complications during Hemodialysis (HD). The mechanism of intradialytic hypertension is currently unclear. Objective: This research aims to understand the association between excessive Ultrafiltration (UF) and intradialytic hypertension episode and its relationship with changes in endothelin-1 level (ET-1), Asymmetric Dimethylarginine (ADMA) level and Nitric Oxide (NO) level during HD. Methods: This study utilized a case-control design. A sample of one hundred and eleven patients who were already undergoing maintenance HD for more than three months was included. Serum levels of NO, ET-1, and ADMA were examined before and after HD; samples were followed by as much as six times consecutive HD session, in which ultrafiltration and blood pressure during HD were noted. Results: From 112 samples obtained, 32.1% (36/112) had intradialytic hypertension. Using regression analysis, we found a significant association between changes in NO levels and intradialytic hypertension. We found a significant association between excessive UF and intradialytic hypertension (p=0.001), adjusted OR=5.17. Path analysis showed the existence of a significant relationship between UF volume during HD and intradialytic hypertension (CR 5.74; p&lt;0.01), as well as a significant relationship between UF volume during HD and NO levels (CR -3.70: p&lt;0.01). There was a direct relationship between NO serum levels with intradialytic hypertension (CR -7.08: p&lt;0.01). Conclusion: Excessive UF during HD plays a role in intradialytic hypertension episode through decreased NO serum levels. There was no clear role of ADMA and ET-1 serum levels on intradialytic hypertension episode.

The role of asymmetric dimethylarginine in the development of arterial&#x0D; hypertension.

The results of numerous studies of recent decades confirm the crucial role of vascular endothelium in regulating vascular homeostasis. A plethora of recent studies have shed light on the clinical significance of endothelial dysfunction in essential hypertension. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor. At present, it is considered as a generally recognized marker of endothelial dysfunction by most researchers. In vitro experiments showed that ADMA inhibits endothelium-dependent arterial relaxation, increases the level of indicators characterizing the degree of oxidative stress in endothelial cells, enhances the synthesis of the superoxide anion radical by endothelial cells. The molecular mechanisms described above, activated with an increase in the concentration of ADMA, cause various disturbances in the function of the cardiovascular system, which gave grounds to consider the level of ADMA as a criterion and risk factor for the development of cardiovascular diseases. Thus, ADMA plays a key role in the development and progression of CVD associated with a spectrum of diseases and pathological conditions characterized by a disturbance in NO production. Despite clinical and experimental confirmation of the relationship between the increase in ADMA in plasma and the development of cardiovascular events, the unambiguous etiopathogenetic role of ADMA in CVD requires further research. In order to accurately answer the question of whether ADMA is an etiological factor or a biological marker of CVD, additional analysis is needed to study the biochemical, genetic and pharmacological aspects of ADMA metabolism, the results of which are presented in this article.

Relationship of asymmetric dimethylarginine levels with disease severity and pulmonary hypertension in chronic obstructive pulmonary disease

Background:Asymmetric dimethylarginine (ADMA) has emerged as a risk marker for many conditions related to pulmonary hypertension (PH); however, little is known about ADMA and symmetric dimethylarginine (SDMA) plasma concentrations in chronic obstructive pulmonary disease (COPD). Our interest centers on the role of ADMA in regulation of endothelial function in COPD and secondary PH. The aim of the present study was to evaluate the serum ADMA, SDMA, and L-arginine concentrations in COPD and its association with PH.Methods:Patients with diagnosis of COPD underwent pulmonary function tests, echocardiography, and laboratory investigations including ADMA, SDMA, and L-arginine.Results:Serum concentrations of ADMA, SDMA, and L-arginine tend to increase as COPD progresses. Patients with PH had higher concentrations of ADMA, SDMA, and L-arginine compared to cases with normal pulmonary arterial pressure (PAP); the difference was not statistically significant.Conclusions:Our results show that increased ADMA, SDMA, and L-arginine concentrations are associated with increased PAP measurements in patients with COPD, however, the relationship is not statistically significant.

Role of DDAH/ADMA pathway in TGF-β1-mediated activation of hepatic stellate cells.

Asymmetric dimethylarginine (ADMA) is catalyzed by the enzyme dimethylarginine dimethylaminohydrolase (DDAH) in humans, and the role for ADMA has been associated with hepatic fibrogenesis. Transforming growth factor‑β (TGF‑β) has been shown to mediate the myofibroblastic transformation of quiescent hepatic stellate cells (HSCs), a pivotal step in liver fibrogenesis. However, the underlying molecular mechanisms are not well understood. Accumulation of ADMA due to low activity of DDAH has been reported to be associated with liver damage and hepatic fibrosis. In this study, the role of the DDAH/ADMA pathway in the TGF‑β1‑induced HSC activation was assessed. Freshly harvested primary HSCs from rat liver were used in this study. It was demonstrated that TGF‑β1 treatment significantly suppressed the DDAH protein expression and activity, and increased levels of ADMA in the culture medium of rat primary HSCs. Notably, the TGF‑β1‑mediated effects on DDAH/ADMA were significantly abrogated by the p38 mitogen activated protein kinase specific inhibitor, SB203580. Furthermore, it was demonstrated that excessive ADMA led to an increase in the number of TGF‑β1‑positive HSCs and induced the expression of α‑smooth muscle actin and collagen type I in rat primary HSCs. In addition, rat primary HSCs exposed to excessive ADMA showed a significant increase in the expressions of α‑SMA and collagen typeI. Finally, it was revealed that ADMA treatment promoted the proliferation of rat primary HSCs. In conclusion, the results obtained from the study suggest a potentially novel role for the ADMA/DDAH1 signaling pathway in TGF‑β1‑induced HSC activation, and along with the studies of others, suppression of the ADMA/DDAH1 pathway may be an alterative approach for the treatment of liver fibrosis.

Cellular interactions between L-arginine and asymmetric dimethylarginine: Transport and metabolism.

This study was aimed to examine the effect of L-arginine (ARG) exposure on the disposition of asymmetric dimethylarginine (ADMA) in human endothelial cells. Although the role of ADMA as an inhibitor of endothelial nitric oxide synthase (eNOS) is well-recognized, cellular interactions between ARG and ADMA are not well-characterized. EA.hy926 human vascular endothelial cells were exposed to 15N4-ARG, and the concentrations of 15N4-ARG and ADMA in the cell lysate and incubation medium were determined by a liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS) assay. Nitric oxide (NO) production was estimated by utilizing cumulative nitrite concentration via a fluorometric assay. Cells incubated with 15N4-ARG exhibited enhanced nitrite production as well as 15N4-ARG cellular uptake. These changes were accompanied by a decrease in cellular ADMA level and increase in extracellular ADMA level, indicating an efflux of endogenous ADMA from the cell. The time courses of ADMA efflux as well as nitrite accumulation in parallel with 15N4-ARG uptake were characterized. Following preincubation with 15N4-ARG and D7-ADMA, the efflux of cellular 15N4-ARG and D7-ADMA was significantly stimulated by high concentrations of ARG or ADMA in the incubation medium, demonstrating trans-stimulated cellular transport of these two amino acids. D7-ADMA metabolism was inhibited in the presence of added ARG. These results demonstrated that in addition to an interaction at the level of eNOS, ARG and ADMA may mutually influence their cellular availability via transport and metabolic interactions.

Exhaled nitric oxide dynamics in asthmatic reactions induced by diisocyanates.

Isocyanate-induced asthmatic reactions are associated with delayed increase in fractional exhaled nitric oxide measured at expiratory flow of 50mL/s (FeNO50), a biomarker of airway inflammation. The time course of FeNO increase is compatible with the activation of NO synthase, but the origin of NO production in the lung is undetermined. The aim of this study was to define the dynamics of airway and alveolar NO during specific inhalation challenge (SIC) with isocyanates and the role of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase. Spirometry, exhaled NO parameters (FeNO50, bronchial wall NO concentration, NO airway diffusing capacity, NO flux to luminal space, alveolar NO) and ADMA levels in exhaled breath condensate were measured before and at intervals up to 24h after exposure to isocyanates. The results were compared between 17 SIC-positive and eight SIC-negative subjects. A significant FeNO50 increase in SIC-positive subjects was detected 24h after exposure and was associated with the augmented NO flux from airway wall to the lumen, whereas airway NO diffusion and alveolar NO were not affected. The changes in NO dynamics were specific for the subjects who developed an asthmatic reaction, but were independent from the pattern and magnitude of bronchoconstriction. There was no evidence that exhaled NO is modulated by the changes in ADMA concentration. Because isocyanate-induced increase in FeNO50 was almost exclusively determined by the increase in NO flux, the use of FeNO50 appears adequate to monitor the exhaled NO dynamics during SIC. FeNO50 measurement may provide additional information to spirometry, because bronchoconstriction and airway inflammatory responses are dissociated.

Role of Asymmetrical Dimethylarginine in Diabetic Microvascular Complications.

Microvascular complications are the leading causes of acquired blindness, end-stage renal failure, and varieties of neuropathy associated with diabetes. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is involved in endothelial dysfunction, oxidative stress, and inflammation associated with the progression of diabetic microvascular complications. Elevated ADMA has been detected in experimental animals and patients with diabetic microangiopathy like retinopathy, nephropathy, and neuropathy. In the review, we focus on the role of ADMA in the pathobiology of major microvascular complications of diabetes.

P.1.j.026 - Serum neuron-specific enolase, protein S100B and C-reactive protein levels and cognitive performance in patients with schizophrenia

Nitric oxide (NO) is thought to be involved in the pathogenesis of schizophrenia as well as many neuropsychiatric disease. Asymmetric dimethylarginine (ADMA) reduces the level of NO by inhibiting nitric oxide synthase (NOS) enzyme. In this study it is aimed to be investigated ADMA in patients with first-episode schizophrenia. In this study, according to DSM-IV diagnostic criteria for schizophrenia-like psychotic disorder, 49 male first-episode schizophrenia patients—whose mean age was 23.4±3.5 year—and age and education matched 30 healthy male subjects were included for comparison. ADMA levels of the patients were measured before and after 2 months of therapy. In order to rule out the conditions that may affect the levels of ADMA, people whose physical examination and laboratory findings were within normal range were included in the study. In this study plasma ADMA levels of first-episode schizophrenia patients and control group were 3.6±1.5 µmol/L and 1.02±1.02 respectively. After 2 months of antipsychotic treatment plasma ADMA levels of the schizophrenia patients decreased compared to baseline. There was no relationship between the ADMA levels and the clinical severity of the disease. It is considered to be the role of ADMA in the etiopathogenesis of schizophrenia.